This is a Competing Continuation for the grant titled: Genetic Differences in Alzheimer's Cases and Controls. The broad goal or objective of the grant remains to evaluate diagnostic markers for Alzheimer's disease, assess their relation to epidemiologic/genetic risk factors and to identify and define possible subtypes of Alzheimer's disease. The principal marker of interest for this phase of the project is beta-amyloid deposition in skin of Alzheimers cases and controls (this will require a small 5mm punch biopsy from the forearm, blood samples will also be requested each subject can give one or both). As a possible mechanism for beta-amyloid deposition we will investigate differences In platelets of AD cases and controls specifically, concerning APP differences and response to stimulation. Other markers to be tested include Amyloid Precursor Protein (APP) genotypes, and Apolipoprotein CII genotypes. Beta-amyloid will be evaluated not only as a diagnostic marker for presenting AD but also as a marker for preclinical disease by obtaining annual cognitive followup of control subjects who tested both positive and negative for the marker. This marker will also be evaluated as a familial trait, if the initial results indicate that it does in fact function as a marker. Epidemiologic risk factor data will be ( or has been) obtained. Risk factor data will be examined for its relation to AD and to the various markers and their interactions. This may lead to the identification of clinically distinct subtypes of the disease and provide clues to the etiology and pathogenesis. Finally, we will determine the occurrence of the gene for Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome, two transmissible forms of dementia, among our clinically diagnosed AD cases and randomly selected controls. All cases and controls are members of Group Health Cooperative (GHC) which functions as the population base; all cases are/were newly diagnosed by the Alzheimer's Disease Patent Registry (UOl AGO6781-04). Control subjects are selected at random from the membership and must be cognitively intact, free of neurologic disease, and of similar age and sex as the cases. Over 200 subjects have been enrolled in the initial grant period and will be available to participate in the current investigation. Approximately 400 to 500 additional subjects are expected to participate in one or more phase of the renewal application.